Nephrotic Syndrome (NS) from Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Nephropathy (MN) is a group of rare diseases that can cause catastrophic complications and end stage kidney disease. Despite their rarity, this disease group generates an enormous individual and societal economic burden. The currently employed, histopathology-based taxonomy of NS is inadequate and fails to capture the molecular bases of these diseases. Recent discoveries, which have identified causal genes in familial [mendelian] FSGS, the target podocyte antigen characterizing MN, and the association of APOL1 variants with FSGS histology in African American NS patients, provides indisputable evidence that multiple, unique disease mechanisms can present with indistinguishable histopathology. A Precision Medicine approach is necessary to identify and to execute specific therapies for each of the many unique glomerular diseases that result in NS. This requires understanding of the molecular bases of glomerular disease. Over the past 4 years NEPTUNE has advanced the care of NS patients by establishing a robust investigative infrastructure encompassing 21 sites, which has recruited more than 500 rigorously phenotyped NS patients, with biological materials and associated detailed clinical data. In addition, NEPTUNE has established robust training and ancillary study programs open to all interested investigators. In this renewal proposal, we propose to leverage these resources to further associate clinically meaningful endpoints with shared and specific genetic, molecular and structural features of glomerular diseases to generate a new, molecular NS taxonomy that will permit discovery of novel therapeutic targets and trial design. Two cohort studies will enroll NS individuals with (1) severe NS enriched for African Americans and (2) pediatric cohort with NS at time of first presentation prior to biopsy. These cohorts will add critical segments of NS disease phenotypes to reflect the full NS disease spectrum in NEPTUNE. Training and pilot programs will continue to leverage the unique resources in NEPTUNE and outreach in conjunction with patient interest group NephCure engaging lay communities, clinicians and scientists to advance NS research